Ethers of substituted hydroxymethylpyrazines

ABSTRACT

Ethers of substituted hydroxymethylpyrazines, such as, for instance, the compound 2-methoxymethyl-5-methylpyrazine-4-oxide. The compounds exhibit elevated lipid-lowering activity, especially anti-lipolytic activity (decrease of plasma-free fatty acids), triglyceride-lowering activity, cholesterol-lowering activity, and plasma-phospholipid-lowering activity.

DESCRIPTION

The present invention relates to ethers of substitutedhydroxymethylpyrazine derivatives, to a process for their preparationand to pharmaceutical compositions containing them.

The compounds of the invention have the following general formula (I)##STR1## wherein each of the groups R, R₁ and R₂, which may be the sameor different, represents a hydrogen atom, a C₁ -C₆ alkoxy or C₁ -C₆alkyl group, and R₃ represents a straight or branched chain, saturatedor unsaturated, C₁ -C₈ aliphatic hydrocarbon group.

Also the possible isomers of the compounds of formula (I), theirmixtures and the metabolites and the metabolic precursors andbioprecursors of the compounds of formula (I) are included in the scopeof the present invention. The alkyl and alkoxy groups may be branched orstraight chain groups.

When one of R, R₁ and R₂ is C₁ -C₆ alkoxy, it is preferably C₁ -C₄alkoxy, in particular methoxy or ethoxy.

When one of R, R₁ and R₂ is C₁ -C₆ alkyl, it is preferably C₁ -C₃ alkyland more preferably methyl.

R₃ is preferably a branched or straight chain saturated C₁ -C₈ aliphatichydrocarbon group, in particular C₁ -C₆ alkyl, preferably methyl orethyl.

A preferred class of compounds is that represented by the compounds offormula (I), wherein R and R₂ are both hydrogen, R₁ is C₁ -C₆ alkyl andR₃ is C₁ -C₆ alkyl.

More preferred compounds of the invention are the compounds of formula(I) wherein R and R₂ are both hydrogen, R₁ is C₁ -C₃ alkyl and R₃ is C₁-C₄ alkyl; and more particularly the compounds of formula (I), wherein Rand R₂ are both hydrogen, R₁ is methyl and R₃ is methyl or ethyl.

Examples of particularly preferred compounds of the invention are:

2-methoxymethyl-5-methylpyrazine-4-oxide;

2-ethoxymethyl-5-methylpyrazine-4-oxide;

2-n-propyloxymethyl-5-methylpyrazine-4-oxide;

2-i-propyloxymethyl-5-methylpyrazine-4-oxide;

2-n-butyloxymethyl-5-methylpyrazine-4-oxide;

2-tert-butyloxymethyl-5-methylpyrazine-4-oxide;

2-n-pentyloxymethyl-5-methylpyrazine-4-oxide;

2-n-hexyloxymethyl-5-methylpyrazine-4-oxide.

The compounds of the invention may be prepared by a process comprising:

(a) reacting a compound of formula (II) ##STR2## with a compound offormula (III)

    Y--R.sub.3                                                 (III)

wherein in the above formulae (II) and (III) R, R₁, R₂ and R₃ are asdefined above, and one of the groups X and Y is halogen or the residueof a reactive ester of an alcohol and the other is a group --OM, whereinM is hydrogen or a cation, or

(b) oxidizing a compound of formula (IV) ##STR3## wherein each of R',R'₁ and R'₂, being the same or different, is hydrogen or methyl and R₃is as defined above, so obtaining a compound of formula (I), whereineach of R, R₁ and R₂, being the same or different, is hydrogen or methyland R₃ is as defined above; and, if desired, transforming a compound offormula (I) so produced into another compound of formula (I) and/or, ifdesired, separating a mixture of isomers of compounds of formula (I)into the single isomers.

When one of X and Y is halogen, it is preferably chlorine or bromine.

When one of X and Y is the residue of a reactive ester of an alcohol, itis preferably --O-mesyl or --0-tosyl.

When one of X and Y is a group --OM, M is preferably a cation,preferably an alkali metal cation, for example sodium or potassium.

Thus, when X is halogen or the residue of a reactive ester of analcohol, the compound of formula (II) is reacted with a compound offormula (III) wherein Y is a group --OM; while, when X represents agroup --OM, the compound of formula (II) is reacted with a compound offormula (III) wherein Y is halogen or the residue of a reactive ester ofan alcohol.

The reaction between a compound of formula (II) and a compound offormula (III) may be carried out, for example by using equimolar amountsof the reagents in a solvent such as an aromatic hydrocarbon, preferablybenzene, toluene or xylene; or dimethylformamide, dimethylacetamide,hexamethylphosphortriamide, tetrahydrofuran, dioxane or1,2-dimethoxy-ethane, at temperatures generally from about 20° C. to thereflux temperature of the solvent used, with reaction times generallyfrom about 1 hour to roughly 12 hours. The oxidation of a compound offormula (IV) may, for example, be carried out through organic peracids,e,g; peracetic acid, permaleic acid, monoperphthalic acid orm-chloroperbenzoic acid, prepared in situ by reaction of hydrogenperoxide, for example 30-36% w/v hydrogen peroxide, with thecorresponding acid, at temperatures ranging from about 20° C. to thereflux temperature of the reacting mixture, for reaction times rangingfrom about 1 hour up to about 12 hours. As stated above a compound offormula (I) may be converted, if desired, into another compound offormula (I); this optional process may be carried out by methods knownin themselves.

Also the optional separation of a mixture of isomers into the singleisomers may be carried out by conventional methods.

Compounds of formula (III) are known in the literature. Compounds offormula (II), in which X is a hydroxy group may be obtained by reductionof compounds of formula (V) ##STR4## wherein R,R₁ and R₂ are as definedabove and Z represents a free, salified or esterified carboxy group.

When, in a compound of formula (V), Z is a salified carboxy group, thesalt may be either a salt of an organic base or a salt of an inorganicbase; preferably it is an alkali metal salt.

When, in a compound of formula (V), Z is an esterified carboxy group,the ester may be, for example, an alkyl ester; preferably it is a C₁ -C₆alkoxycarbonyl group, in particular methoxy- or ethoxy-carbonyl.

The reduction of a compound of formula (V), wherein Z is esterifiedcarboxyl, to give a compound of formula (II) wherein X is OH, may, forexample, be carried out using sodium borohydride as reducing agent in asolvent such as methanol, ethanol or isopropanol or a mixture of one ofthese solvents with water in ratios which vary depending on thesolubility of the starting product; the said reduction may also beperformed e.g. using lithium aluminium hydride in inert solvents such asanhydrous diethyl ether or anhydrous tetrahydrofuran at temperatureswhich, in both cases, range from approximately 0° C. to the solventreflux temperature, for reaction times of between approximately 30minutes and approximately 24 hours.

The reduction of a compound of formula (V) wherein Z represents a freecarboxyl group, to give a compound of formula (II), wherein X is OH, ispreferably carried out using lithium aluminium hydride in inert solventssuch as anhydrous ethyl ether, anhydrous diethylene glycol dimethylether, anhydrous tetrahydrofuran or mixtures thereof, or using preformedsolutions of boron hydride in the aforesaid anhydrous solvents, or boronhydride prepared in situ in the reaction medium from sodium boronhydrideand boron trifluoride etherate, preferably in diethylene glycol dimethylether, at temperatures ranging from about 0° C. to the solvent refluxremperature, for reaction times of between approximately 30 minutes and12 hours.

The reduction of a compound of formula (V) wherein Z represents asalified carboxy group, to give a compound of formula (II) wherein X isOH, is preferably carried out in conditions analogous to those employedin the reduction of a compound of formula (V) wherein Z is a freecarboxy group.

The compounds of formula (II) wherein X is --OM, wherein M is a cation,e.g. an alkali metal cation, may be obtained from the correspondingcompounds of formula (II) wherein X is --OH, by treatment with a strongappropriate base, e.g. sodium amide or potassium amide, or by treatmentwith the hydride of an alkali metal, preferably sodium hydride, in theconditions generally used in organic chemistry for this type ofsalification.

The compounds of formula (II) wherein X is halogen may be obtained fromthe corresponding compounds of formula (II) wherein X is --OH by knownmethods, e.g. by treatment with SOCl₂ by conventional methods of organicchemistry, optionally in the presence of a suitable catalyst, forexample ZnCl₂, or by treatment with SOCl₂ or oxalic acid dichloride indimethylformamide, through the formation of a Vilsmeier reagent.

The compounds of formula (II) wherein X is the residue of a reactiveester of an alcohol, e.g. an --O-mesyl or --O-tosyl group, may beprepared from the corresponding compounds of formula (II) wherein X is--OH by known methods, for example by treatment with the suitable acylhalide, preferably chloride, for example with p-toluenesulphonylchlorideor methanesulphonylchloride operating, for instance, in anhydrouspyridine at room temperature.

The compounds of formula (IV) are known [for example they are describedin J.Org.Chem. 26 (3), 2356, (1960)] or may be prepared by known methodsfrom known compounds, for example, as described in the above reference.

Also the compounds of formula (V) are known [for example, they aredescribed in European Journal Medicine Chemistry-Chimica Therapeutica:15, 157, (1980)] or may be prepared by known methods, for example, asdescribed in the above reference.

The compounds of the invention possess an elevated lipid-loweringactivity, in particular an anti-lipolytic activity (decrease of plasmafree fatty acids), triglyceride-, chloresterol- and plasmaphospholipid-lowering activity. The above activities of the compounds ofthe invention were evaluated, on groups of five, six or twelve maleOFA-Ico: SD (IOPS Caw) rats, of average weight 180 g, fasted for 18hours, with water ad libitum.

The compounds to be tested were suspended in Methocel® (0.5% indistilled water) and administered by stomach tube and in doses rangingfrom 1 to 50 mg/Kg body weight, each in a volume of 0.5 ml per 100 g ofbody weight.

The animals were killed at times ranging from the 1^(st) to the 7^(th)hour after treatment.

Groups of animals treated with the suspending agent only (controlgroups) were available for each sampling time.

At the times indicated, treated and control animals were slaughtered andblood collected.

The plasma obtained by centrifugation of the blood samples, withaddition of 1% heparin in saline (0.1 ml for 5 ml of blood), was assayedfor the following variables:

(a) Free fatty acids: by the method of Dole modified by Trout: Dole V.P.--Clin. Invest., 35, 150, (1956); Trout D. L.--J. Lip. Res., 1, 199,(1960)).

(b) Triglycerides: by the method of Mendez; Medez J.--Clin. Chem., 21,N. 6, 768, (1975).

(c) Total cholesterol: by the method of Allain: Allain C. et al.--Clin.Chem., 20, 470, (1974)).

(d) Phospholipids: by the method of Takayama: Takayama M.--Clin. Chim.Acta, 79, 93, (1977).

In particular, the antilipolytic activity for the compound2-methoxymethyl-5-methylpyrazine-4-oxide, coded FCE 21990, was studiedin comparison with the compound2-hydroxymethyl-5-methylpyrazine-4-oxide, coded K 10603, which is themost active compound among those described in U.S. Pat. No. 4,267,327;(Table 1).

The said activity was determined according to the methods describedabove.

For this study one hundred and eight OFA-Ico: SD (IOPS Caw) male ratswere used.

The two compounds were administered orally at a single dose of 50 mg/Kgper os.

Blood samples were collected from the animals at 120 minutes, 180minutes, 300 minutes, 360 minutes after the single administration. Sixanimals were sacrificed for each treatment at the sampling times 120minutes and 180 minutes and twelve animals at the sampling times 300 and360 minutes.

Determination of free fatty acids (FFA) was made, on the plasma samples.

The FFA values for each time and treatment were statistically analyzedas follows: mean and standard error calculation, variance analysis:Winner, B. J. "Statistical Principles in experimental design"--Hill BookCompany (London, San Francisco, Toronto, New York--1962, Pag. 56-62)with a completely randomized experimental design, and finally by theDunnett's test: Biometrics, 20, 482, (1964) for each comparison of thecontrol group versus the two treated groups; (Table 2).

For the sake of brevity, the analysis of variance data are not herereported.

At times 120' and 180' after administration the mean FFA values for thegroups of rats administered FCE 21990 and K 10603 were shown byDunnett's test to differ in a highly significant manner (p≦0.01) fromthe corresponding values for the control group, the former being lowerthan the latter.

At time 300', the means of the values for the two treated groups againboth differed from the corresponding control group mean, the formerbeing lower than the latter. Such difference is significant (p≦0.05) forthe group administered K 10603, and highly significant (p≦0.01) for thegroup treated with FCE 21990.

At time 360', the mean for the group administered FCE 21990 againdiffered in a highly significant manner (p≦0.01) from the mean of thecontrol group, the former being lower than the latter.

The mean of the group administered K 10603 did not differ from the meanof the control group.

It can therefore be concluded that the antilipolytic activity of thecompound FCE 21990 remains high up to the time 360': in fact, at thissampling time the mean of the FFA levels of the animals treated withthis compound is lower than that of the control animals, with asignificance level of p≦0.01.

The antilipolytic activity of the compound K 10603 is shorter-lasting:at time 300' the means of the FFA values after administration of thiscompound is lower than the mean of the controls, with a significancelevel p≦0.05.

At time 360' the mean of the FFA values after administration of K 10603does not differ from that of the control animals, meaning that theantilipolytic effect has ceased.

As it is of very great importance in therapy with antilipolytic agentsthat their activity be protracted over time as long as possible, theforegoing experimental data clearly demonstrate the progress made withthe compound FCE 21990.

                  TABLE 1                                                         ______________________________________                                        Plasma levels of free fatty acids (FFA,                                       expressed as μmoles %) in rats at                                          various times (in minutes) after treatment                                           Dose                                                                          mg/Kg FFA μmoles % Means ± S.E.                                  Treatment                                                                              per os  120'     180'   300'   360'                                  ______________________________________                                        Controls (*)                                                                           --      57.5 +   62.8 + 66.6 + 71.7 ±                                              5.9      4.4    3.2    5.2                                   FCE 21990                                                                              50      15.0 ±                                                                              17.8 ±                                                                            39.3 ±                                                                            39.2 ±                                              2.3      1.1    3.6    5.2                                   K 10603  50      13.7 ±                                                                              17.7 ±                                                                            50.9 ±                                                                            77.5 ±                                              1.2      2.6    6.2    6.9                                                    n = 6    n = 6  n = 12 n = 12                                ______________________________________                                         (*) Methocel 0.5% in distilled water, 5 ml/Kg per os                          n = number of animals for each treatment                                 

                  TABLE 2                                                         ______________________________________                                        Results of Dunnett's test on the values of FFA                                reported in Table 1                                                           Sampling                                                                      time in                                                                       minutes Comparisons              Result                                       ______________________________________                                        120'    Controls → FCE 21990                                                                   50 mg/Kg per os                                                                            HS                                               Controls → K 10603                                                                     50 mg/Kg per os                                                                            HS                                       180'    Controls → FCE 21990                                                                   50 mg/Kg per os                                                                            HS                                               Controls → K 10603                                                                     50 mg/Kg per os                                                                            HS                                       300'    Controls → FCE 21990                                                                   50 mg/Kg per os                                                                            HS                                               Controls → K 10603                                                                     50 mg/Kg per os                                                                            S                                        360'    Controls → FCE 21990                                                                   50 mg/Kg per os                                                                            HS                                               Controls → K 10603                                                                     50 mg/Kg per os                                                                            NS                                       ______________________________________                                         NS = not significant (p > 0.05)                                               S = significant (p ≦ 0.05)                                             HS = highly significant (p ≦ 0.01)                                

In view of their high lipid-lowering activity, these new compounds areuseful in the therapy of primary and secondary hyperlipidaemias.

In particular, because of their antilipolytic activity they can reducethe incidence of ventricular arrhythmias in infarct patients (Rowe H.J., 1975, LANCET 1, 295).

They may be administered in a variety of dosage forms, e.g. orally inthe form of tablets, capsules, sugar- or film-coated tablets, liquidsolutions or suspensions; rectally, in the form of suppositories;parenterally, e.g. intramuscularly or by intravenous injection orinfusion.

The dosage depends on the age, weight, conditions of the patient andadministration route; for example the dosage adopted for oraladministration in adults ranges from about 50 to about 150 mg pro dose,from 1 to 3 times daily, preferably from 50 to 100 mg pro dose 1-3 timesa day.

The toxicity of the compounds of the invention was found to be quitenegligible and therefore they can be safely used in therapy. Theevaluation of the toxicity (as orientative acute toxicity, i.e. LD₅₀),was carried out, e.g., as follows: nine hours food-deprived mice weretreated orally with single administration of increasing doses, thenhoused and normally fed; the LD₅₀ was assessed on the seventh day aftertreatment.

For example, the following data were obtained:2-methoxymethyl-5-methylpyrazine-4-oxide: LD₅₀ >800 mg/Kg2ethoxymethyl-5-methylpyrazine-4-oxide: LD₅₀ >800 mg/Kg.

The scope of this invention includes also pharmaceutical compositionscomprising a compound of formula (I) which may, if desired, be in anyisomeric form, in association with a pharmaceutically acceptableexcipient (which can be a carrier or diluent).

The pharmaceutical compositions containing the compounds of theinvention are usually prepared by conventional methods and administeredin a pharmaceutically suitable form.

For example, the solid oral forms may contain, together with the activecompound, diluents, e.g., lactose, dextrose, saccharose, cellulose, cornstarch or potato starch; lubricants, e.g. silica, talc, stearic acid,magnesium or calcium stearate, and/or polyethylene glycols; bindingagents, e.g. starches, arabic gums, gelatin, methylcellulose,carboxymethyl cellulose or polyvinyl pyrrolidone; disaggregating agents,e.g. a starch, alginic acid, alginates or sodium starch glycolate;effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as,lecithin, polysorbates or laurylsulphates; and in general, non-toxic andpharmacologically inactive substances generally used in pharmaceuticalformulations. Said pharmaceutical preparations may be manufactured inknown manner, for example, by means of mixing, granulating, tabletting,sugar-coating, or film-coating processes. The liquid dispensions fororal administration may be e.g. solutions, syrups, emulsions orsuspensions. The solutions for oral administration may contain ascarrier, for example, water with a suitable amount of a dyestuffs and/orsweeteners agents. The syrups may contain as carrier, for example,saccharose or saccharose with glycerine and/or mannitol and/or sorbitol;in particular, a syrup to be administered to diabetic patients cancontain as carriers only products not metabolizable to glucose, ormetabolizable in only very small amounts to glucose, such as sorbitol.

The suspensions and the emulsions may contain as carrier, for example, anatural gum, agar, sodium alginate, pectin, methylcellulose,carboxymethylcellulose, or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may containtogether with the active compound a pharmaceutically acceptable carrier,e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propyleneglycol, and if desired, a suitable amount of lidocaine hydrochloride.The solutions for intravenous injections or infusions may contain ascarrier, for example, sterile water or preferably they may be in theform of sterile, aqueous, isotonic saline solutions.

The suppositories may contain, together with the active compound, apharmaceutically acceptable carrier, e.g. cocoabutter, polyethyleneglycol, a polyoxyethylene sorbitan fatty acid ester surfactant orlecithin.

The following Examples serve to illustrate the invention. The I.R.spectrum of the compounds was measured in solid phase (KBr) or in Nujolsolution or in a solution of a suitable solvent such as CHCl₃, using aPerkin-Elmer 125 spectrophotometer.

The N.M.R. Spectrum was measured preferably in solution of dimethylsulphoxide-d₆ or of CDCl₃, using a 90 M-hertz Bruker HFX apparatus.

The R_(f) Values were determined by thin layer chromatography onready-to-use silica gel plates of 0.25 mm coating thickness.

EXAMPLE 1

A solution of 2-hydroxymethyl-5-methylpyrazine-4-oxide (2.1 g) inanhydrous dimethylformamide (10 ml) was treated with a suspension ofsodium hydride (0.4 g) in anhydrous dimethylformamide (5 ml).

The reaction mixture was stirred at room temperature until the hydrogenproduction was ceased, then a solution of methyl iodide (2.5 g) inanhydrous dimethylformamide (10 ml) was added portionwise.

After two hours stirring at room temperature, the reaction mixture wasevaporated to dryness under vacuum and the residue was taken up withwater (50 ml) and repeatedly extracted with diethyl ether. The organicphase was washed with water, dried and evaporated to dryness. Theresidue, treated with n-pentane, gave2-methoxymethyl-5-methylpyrazine-4-oxide, (1.6 g) as white solid, m.p.69°-72° C.

    ______________________________________                                        Analysis:                                                                     Found:             C 53.92; H 6.52; N 17.92                                   calculated for C.sub.7 H.sub.10 N.sub.2 O.sub.2 :                                                C 54.53; H 6.54; N 18.17                                   T.L.C. (diethylether:methanol = 180:20) R.sub.f = 0,31                        I.R. (CHCl.sub.3)                                                                          ν 3120 cm.sup.-1 (CH aromatics)                                            ν 3080 cm.sup.-1                                                           ν 2940 cm.sup.-1 (CH aliphatics)                                           ν 2900 cm.sup.-1                                                           ν 2830 cm.sup.-1                                                           ν 1600 cm.sup.-1 (CC, CN)                                                  ν 1520 cm.sup.-1                                                            ##STR5##                                                        N.M.R. (CDCl.sub.3): δ ppm                                                              2.48 (s; 3H; CH.sub.3C)                                                       3.52 (2; 3H; OCH.sub.3)                                                       4.58 (s; 2H; CH.sub.2OCH.sub.3)                                                ##STR6##                                                                     8.44 (s; 1H; CHN)                                             ______________________________________                                    

The following compounds were similarly obtained:

    ______________________________________                                        2-ethoxymethyl-5-methylpyrazine-4-oxide (semi-solid oil)                      ______________________________________                                        Analysis:                                                                     Found:             C 56.54; H 7.06; N 16.21                                   Calculated for C.sub.8 H.sub.12 N.sub.2 O.sub.2 :                                                C 57.13; H 7.19; N 16.65                                   T.L.C.: (diethylether:methanol = 180:20) R.sub.f ≃ 0.4          N.M.R. (CDCl.sub.3): δ p.p.m.                                                           1.27 (t; 3H; CH.sub.2CH.sub.3)                                                 ##STR7##                                                                     3.65 (q; 2H; CH.sub.2CH.sub.3)                                                 ##STR8##                                                                      ##STR9##                                                                     8.40 (s large; 1H; CHN)                                       I.R. (CHCl.sub.3):                                                                         ν 2930 cm.sup.-1 (CH aliphatics)                                           ν 2870 cm.sup.-1                                                           ν 1600 cm.sup.-1 (CC, CN)                                                  ν 1515 cm.sup.-1                                                            ##STR10##                                                                    ν 1110 cm.sup.-1 (COC)                                        ______________________________________                                        2-ethoxymethyl-5-n-propylpyrazine-4-oxide (semi-solid oil)                    ______________________________________                                        Analysis:                                                                     Found:             C 60.59; H 8.07; N 14.11                                   Calculated for C.sub.10 H.sub.16 N.sub.2 O.sub.2 :                                               C 61.20; H 8.21; N 14.27                                   I.R. (CHCl.sub.3):                                                                         ν 2940 cm.sup.-1 (CH aliphatics)                                           ν 2900 cm.sup.-1                                                           ν 2830 cm.sup.-1                                                           ν 1600 cm.sup.-1 (CC; CN)                                                  ν 1515 cm.sup.-1                                                            ##STR11##                                                       ______________________________________                                    

2-n-propyloxymethyl-5-methylpyrazine-4-oxide;

2-i-propyloxymethyl-5-methylpyrazine-4-oxide;

2-n-butyloxymethyl-5-methylpyrazine-4-oxide;

2-tert-butyloxymethyl-5-methylpyrazine-4-oxide;

2-n-pentyloxymethyl-5-methylpyrazine-4-oxide; and

2-n-hexyloxymethyl-5-methylpyrazine-4-oxide.

EXAMPLE 2

2-Hydroxymethyl-5-methylpyrazine-4-oxide (3.5 g) was dissolved understirring in a solution of 8 ml of thionyl chloride in 20 ml of drybenzene containing 0.5 g of ZnCl₂, keeping the temperature below 30° C.The reaction mixture was cautiously warmed 3 hours at 60° C., thencooled to room temperature, and filtered. The solvent was evaporatedunder reduced pressure. The oily residue was dissolved in a solution ofsodium methoxide in methyl alcohol, previously prepared dissolving 0.6of sodium in 30 ml of methyl alcohol. After refluxing 4 hours, thereaction solution was cooled at room temperature, filtered andevaporated to dryness. The residue was taken up with water andrepeatedly extracted with ethyl ether. The organic phase was washed withwater, dried and the solvent was evaporated to dryness; the residuetreated with pentane gave 2-methoxymethyl-5-methylpyrazine-4-oxide (1.5g), m.p. 69°-72° C.

The following compounds were similarly obtained:

2-ethoxymethyl-5-n-propylpyrazine-4-oxide;

2-ethoxymethyl-5-methylpyrazine-4-oxide;

2-n-propyloxymethyl-5-methylpyrazine-4-oxide;

2-i-propyloxymethyl-5-methylpyrazine-4-oxide;

2-n-butyloxymethyl-5-methylpyrazine-4-oxide;

2-tert-butyloxymethyl-5-methylpyrazine-4-oxide;

2-n-pentyloxymethyl-5-methylpyrazine-4-oxide; and

2-n-hexyloxymethyl-5-methylpyrazine-4-oxide.

EXAMPLE 3

2-ethoxymethyl-5-methylpyrazine [J.O.C. 26 (3), 2356, (1960)] (1.0 gr)was heated with 36% w/v hydrogen peroxide (0.7 ml) in glacial aceticacid (2.15 ml) for 5 hours at 60° C., then 0.7 ml of 36 w/v hydrogenperoxide were added and the reaction mixture was heated for 5 hours.

The solution was concentrated under reduced pressure to about one thirdof the starting volume and diluted with an equal amount of cold water.The solution was made alkaline with 20% sodium hydroxide and extractedwith chloroform.

The combined extracts were dried, the solvent stripped under reducedpressure and the residue was purified by column chromatography oneluting with C₂ H₅ OH: CH₃ OH═190:5 to give2-ethoxymethyl-5-methylpyrazine-4-oxide (semi-solid oil).

Analysis:

Found: C 56.80; H 6.95; N 16.35, Calculated for C₈ H₁₂ N₂ O₂ : C 57.13;H 7.19; N 16.65.

The following compound where similarly obtained:

2-methoxymethyl-5-methylpyrazine-4-oxide;

2-n-propyloxymethyl-5-methylpyrazine-4-oxide;

2-i-propyloxymethyl-5-methylpyrazine-4-oxide;

2-n-butyloxymethyl-5-methylpyrazine-4-oxide;

2-tert-butyloxymethyl-5-methylpyrazine-4-oxide;

2-n-pentyloxymethyl-5-methylpyrazine-4-oxide; and

2-n-hexyloxymethyl-5-methylpyrazine-4-oxide.

The starting materials for use in Examples 1 and 2 may be prepared inaccordance with the following Examples 4 and 5.

EXAMPLE 4

To a solution of 2-carbomethoxy-5-methylpyrazine-4-oxide (6.3 g) in amixture of water (50 ml) and methyl alcohol (25 ml) cooled to atemperature between 0° C. and 5° C., sodium boronhydride (4.25 g) wasadded in portions, under stirring and maintaining the temperature below10° C. The reaction mixture was stirred for 2 hours at room temperature,the solvent then evaporated under vacuum and the residue extractedseveral times with methanol under heating. After evaporation to dryness,the residue was taken up with CHCl₃ and filtered.

By first dehydrating the chloroform extracts and then evaporating todryness, 4 g (76%) of 2-hydroxymethyl-5-methylpyrazine-4-oxide, m.p.110°-111° C., were obtained.

Analysis:

Found: C, 51.37; H, 5.76; N, 19.94, Calculated for C₆ H₈ N₂ O₂ : C,51.42; H, 5.75; N, 19.99.

T.L.C.: mobile phase: CHCl₃ :CH₃ OH=170:30 R_(f) =0.38

N.M.R. (CDCl₃) δ ppm (2.42 3H s), (4.36 1H broad band), (4.74 2H s),(8.3 1H s), (8.38 1H s).

The 2-carbomethoxy-5-methylpyrazine-4-oxide used as starting materialwas prepared, with a yield of 83% from2-carboxy-5-methylpyrazine-4-oxide refluxed for twelve hours inanhydrous methanol in the presence of boron trifluoride etherate, m.p.146°-148° C.

Analysis:

Found: C, 49.91; H, 4.82; N, 16.58, Calculated for C₇ H₈ N₂ O₃ : C,50.00; H, 4.80; N, 16.65.

T.L.C. mobile phase: CHCl₃ :CH₃ OH:NH₂ OH=190:10:0.5 R_(f) =0.61

EXAMPLE 5

To a solution of 2-carboxy-5-methylpyrazine-4-oxide (1.5 g) indiethylene glycol dimethyl ether (80 ml), a (1 M) solution of diboranein tetrahydrofuran (30 ml) was added at 0° C. under an atmosphere ofnitrogen.

To the reaction mixture, maintained for 3 hours at 0° C. and 1 hour atroom temperature, was cautiously added ethanol (50 ml) and then a 0.5 Msolution of alcoholic KOH (25 ml). The resultant solution afterevaporation at reduced pressure, was taken up with chloroform soobtaining, after evaporation to dryness, 1.2 g of2-hydroxymethyl-5-methylpyrazine-4-oxide.

Formulation Examples

Formulation I: Tablet

Tablets, each weighing 300 mg and containing 100 mg of the activesubstance are manufactured as follows:

    ______________________________________                                        Composition (for 10,000 tablets)                                              ______________________________________                                        2-Methoxymethyl-5-methylpyrazine-4-oxide                                                                1000   g                                            Lactose                   1420   g                                            Corn starch               475    g                                            Talc powder               75     g                                            Magnesium stearate        30     g                                            ______________________________________                                    

2-methoxymethyl-5-methylpyrazine-4-oxide, lactose, and half of the cornstarch are mixed; the mixture is then forced through a sieve of 0.5 mmopenings. Corn starch (18 g) is suspended in warm water (180 ml). Theresulting paste is used to granulate the powder. The granules are dried,comminuted on a sieve of sieve size 1.4 mm, then the remaining quantityof starch, talc and magnesium stearate is added, carefully mixed, andprocessed into tablets using punches of 10 mm diameter.

Formula II: intramuscular injection solution

An injectable pharmaceutical composition was manufactured by dissolving50-100 mg of 2-methoxymethyl-5-methylpyrazine-4-oxide in sterile wateror sterile aqueous normal saline solution (1-2 ml).

Formulation III: Capsule

By the usual pharmaceutical techniques, capsules having the followingcomposition were prepared:

    ______________________________________                                        2-Methoxymethyl-5-methylpyrazine-4-oxide                                                                50     mg                                           Lactose                   298    mg                                           Corn Starch               50     mg                                           Magnesium stearate        2      mg                                           ______________________________________                                    

Formulation IV: Suppository

By the usual pharmaceutical techniques, suppositories having thefollowing composition were prepared:

    ______________________________________                                        2-Methoxymethyl-5-methylpyrazine-4-oxide                                                                0.05   g                                            Lecithin                  0.07   g                                            Cacao butter              0.88   g                                            ______________________________________                                    

We claim:
 1. A method of inducing an anti-lipolytic effect in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound of the formula ##STR12## wherein each of the groups R, R₁ and R₂, which may be the same or different, is a hydrogen atom or a C₁ -C₆ straight or branched chain alkoxy or a C₁ -C₆ straight or branched chain alkyl group.
 2. Method of claim 1, wherein R and R₂ are both hydrogen and R₁ is alkyl.
 3. Method of claim 2, wherein R₁ is a C₁ -C₃ straight or branched chain alkyl.
 4. A method of inducing an anti-lipolytic effect in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of 2-methoxymethyl-5-methylpyrazine-4-oxide.
 5. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula ##STR13## wherein each of the groups R, R₁ and R₂, which may be the same or different, is a hydrogen atom, a C₁ -C₆ straight or branched chain alkoxy group or a C₁ -C₆ straight or branched chain alkyl group, and a pharmaceutically acceptable carrier and/or diluent.
 6. Composition of claim 5, wherein R and R₂ are both hydrogen and R₁ is alkyl.
 7. Composition of claim 6, wherein R₁ is a C₁ -C₃ straight or branched chain alkyl.
 8. A pharmaceutical composition comprising a therapeutically effective amount of 2-methoxymethyl-5-methylpyrazine-4-oxide, and a pharmaceutically acceptable carrier and/or diluent. 